Pharmaceutical composition comprising selexipag

Abstract

The invention relates to aqueous pharmaceutical compositions comprising the compound 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(methylsulfonyl) acetamide; glycine; polysorbate 20; and an aqueous phosphate buffer, wherein the relative amounts are as described in the description, wherein the pH of said pharmaceutical composition is between about 7 and 8; to lyophilized pharmaceutical compositions prepared from said aqueous compositions, and to reconstituted aqueous compositions thereof which are suitable for i.v. administration. The invention further relates to processes for the preparation of said compositions, and to their use for the treatment of diseases and disorders which are related to IP receptor.

The invention claimed is: 
     
       1. An aqueous pharmaceutical composition comprising:
 about 0.1 g/kg to 1 g/kg of the compound 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(methylsulfonyl)acetamide: 
 
       
         
           
           
               
               
           
         
         about 2.5 ww % to 10 ww % of a bulking agent which is glycine; 
         about 0.05 ww % to 0.4 ww % of a detergent which is polysorbate 20; and 
         an aqueous phosphate buffer, wherein the total amount of said phosphate buffer is about 5 mmol/kg to 20 mmol/kg; 
       
       wherein the pH of said aqueous pharmaceutical composition is between about 7 and 8. 
     
     
       2. An aqueous pharmaceutical composition according to  claim 1 ; comprising:
 about 0.5 g/kg of the compound: 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(methylsulfonyl)acetamide; 
 about 3 ww % to 6 ww % of glycine; 
 about 0.1 ww % to 0.3 ww % of polysorbate 20; and 
 aqueous sodium phosphate buffer, wherein the concentration of said sodium phosphate buffer is about 5 mmol/kg to 20 mmol/kg; 
 
       wherein the pH of said aqueous pharmaceutical composition is 7.5±0.2. 
     
     
       3. An aqueous pharmaceutical composition according to  claim 1 ; comprising
 about 0.5 g/kg of the compound: 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(methylsulfonyl)acetamide; 
 5±0.5 ww % of glycine; 
 about 0.3 ww % of polysorbate 20; and 
 aqueous sodium phosphate buffer, wherein the concentration of said sodium phosphate buffer is about 5 mmol/kg to 20 mmol/kg; 
 
       wherein the pH of said aqueous pharmaceutical composition is 7.5±0.2. 
     
     
       4. An aqueous pharmaceutical composition according to  claim 1 , wherein the compound 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy-N-(methylsulfonyl)acetamide in crystalline form is used for the preparation of said composition. 
     
     
       5. A method for the preparation of a lyophilized pharmaceutical composition; said method pharmaceutical comprising the steps of:
 a) preparing an aqueous pharmaceutical composition according to  claim 1 ; and 
 b) freeze-drying said aqueous pharmaceutical composition to form a cake using a method comprising the steps of:
 i) freezing the aqueous pharmaceutical composition at a first temperature for a period sufficient to transform the liquid formulation into solid state, wherein said first temperature is in the range of about −55° C. to −25° C.; 
 ii) annealing the frozen composition at a second temperature; wherein said second temperature is in the range of about −20° C. to −1° C.; 
 iii) subjecting the frozen composition to a vacuum at a third temperature wherein said third temperature is in the range of about −55° C. to −25° C.; and 
 iv) drying the composition in said vacuum at a fourth temperature wherein said fourth temperature is in the range of about 20° C. to 40° C. 
 
 
     
     
       6. A lyophilized pharmaceutical composition prepared by lyophilizing an aqueous pharmaceutical composition according to  claim 1 . 
     
     
       7. A lyophilized pharmaceutical composition according to  claim 6 ; wherein said lyophilized pharmaceutical composition is in a container. 
     
     
       8. A lyophilized pharmaceutical composition according to  claim 6 ; wherein said lyophilized pharmaceutical composition has a residual water content of less than about 2 ww %. 
     
     
       9. A lyophilized pharmaceutical composition according to  claim 6 ; wherein said lyophilized pharmaceutical composition is chemically stable and physically stable at room temperature and a relative humidity of about 75% or below for at least 6 months. 
     
     
       10. A method for the prevention or treatment of ulcer, digital ulcer, diabetic gangrene, diabetic foot ulcer, pulmonary hypertension, pulmonary arterial hypertension, Fontan disease and pulmonary hypertension associated with Fontan disease, sarcoidosis and pulmonary hypertension associated with sarcoidosis, peripheral circulatory disturbance, connective tissue disease, chronic kidney diseases including glomerulonephritis and diabetic nephropathy at any stage, diseases in which fibrosis of organs or tissues is involved, or respiratory diseases, the method comprising administering a pharmaceutically acceptable amount of a pharmaceutical composition according to  claim 1  to a patient in need thereof. 
     
     
       11. A method for the preparation of a reconstituted pharmaceutical composition; said method comprising the step of reconstituting the lyophilized pharmaceutical composition according to  claim 6  by adding at least one diluent to said lyophilized composition. 
     
     
       12. A reconstituted pharmaceutical composition prepared from a lyophilized pharmaceutical composition according to  claim 6 . 
     
     
       13. A reconstituted pharmaceutical composition according to  claim 12 ; wherein said reconstituted pharmaceutical composition is in a container. 
     
     
       14. A reconstituted pharmaceutical composition according to  claim 12 ; wherein said reconstituted pharmaceutical composition is reconstituted in a reconstitution time of less than about 2 minutes. 
     
     
       15. A reconstituted pharmaceutical composition according to  claim 12 ; wherein said reconstituted pharmaceutical composition is reconstituted using, as diluent, water for injection or saline; wherein the total volume of said reconstituted pharmaceutical composition is between about 2 and 10 mL. 
     
     
       16. A reconstituted pharmaceutical composition according to  claim 12 ; wherein said reconstituted pharmaceutical composition, or a part of said reconstituted pharmaceutical composition, is further diluted; wherein said reconstituted and further diluted pharmaceutical composition contains an amount of about 4.5 μg/mL, 9 μg/mL, 13.5 μg/mL, 18 μg/mL, 22.5 μg/mL, 27 μg/mL, 31.5 μg/mL, or 36 μg/mL of the compound 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(methylsulfonyl)acetamide. 
     
     
       17. A reconstituted and further diluted pharmaceutical composition according to  claim 16 ; wherein said reconstituted and further diluted pharmaceutical composition has an osmolality of below about 1000 mOsmol/kg.